P786: THROMBOSIS AND MENINGOCOCCAL INFECTION RATES IN PEGCETACOPLAN PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA IN THE CLINICAL TRIAL AND POST-MARKETING SETTINGS
Authors: Richard Kelly, Hisakazu Nishimori, Regina Horneff, Peter Hillmen, Jessica Savage, Mohammed Al-Adhami, Stacie Lallier, Gloria Gerber
Journal: HemaSphere (2023)

Topic: 12. Bone marrow failure syndromes incl. PNH - Clinical Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic disease characterized by complement-mediated hemolysis and thrombosis. Before approval of complement inhibitors, thrombosis was the leading cause of death in patients with PNH. Complement inhibitors have subsequently decreased thrombosis rates in patients with PNH, with mortality comparable to age-matched controls. In patients who received the C5 inhibitor (C5i) eculizumab in clinical trials, thrombosis rates decreased from 7.37 events/100 patient-years before eculizumab treatment to 1.07 events/100 patient-years with eculizumab.[1] The C5i ravulizumab had a similar thrombosis rate of 1.38 events/100 patient-years.[2] Inhibiting the complement system increases the risk of life-threatening Neisseria infections, especially N meningitidis. Optimal PNH treatment must decrease complement activity enough to reduce hemolysis and thrombosis without compromising the complement system to an extent that increases infectious risk. Prior studies have estimated the meningococcal infection rate in C5i-treated patients as 0.25 events/100 patient-years.[3] We report thrombosis and meningococcal infection rates with pegcetacoplan, the first C3-targeted therapy approved for adults with PNH. Aims: To determine the rates of thrombosis and meningococcal infections in patients with PNH treated with pegcetacoplan. Methods: We calculated the cumulative patient-year exposure to pegcetacoplan and reviewed events of venous thrombosis and meningococcal infections in 7 clinical trials and in the post-marketing setting. Adults with PNH who completed 1 of 5 trials (PHAROAH [phase 1], PADDOCK [phase 1b], PALOMINO [phase 2a], PEGASUS [phase 3], and PRINCE [phase 3]) were eligible to enroll in an ongoing rollover extension study (NCT03531255). Adolescents with PNH from PIONEER, an ongoing phase 2 open-label study (NCT04901936), were also included in this analysis. The clinical trial protocols and pegcetacoplan labeling required vaccination against Streptococcus pneumoniae, N meningitidis, and Haemophilus influenzae before pegcetacoplan use; the label allows prophylactic antibiotic use if pegcetacoplan must be administered before vaccination. Results: Overall, 464 patients with PNH had experienced a total of 619.4 patient-years of pegcetacoplan exposure in the post-marketing setting (in the US, EU, and rest of the world) and in completed/ongoing clinical trials as of November 13, 2022. In clinical trials, 5 thrombotic events occurred. None were assessed as related to pegcetacoplan by study investigators and all resolved; 3 patients had 1 event each and 1 patient had 2 concurrent events (Table). In the post-marketing setting, 2 patients had 1 thrombotic event each. The overall thrombosis rate was 1.13 events/100 patient-years (clinical trials: 1.22 events/100 patient-years in 409.4 years; post-marketing: 0.95 events/100 patient-years in 210 years). No infections with meningococcal bacteria were reported in more than 619.4 patient-years. Summary/Conclusion: These findings suggest that venous thromboembolism risk reduction ranges may be comparable with pegcetacoplan and C5is in patients with PNH. Proximal complement inhibition with pegcetacoplan may not increase the meningococcal infection risk compared with terminal complement inhibitors. Continued follow-up is required. References: 1. Hillmen P, et al. Blood. 2007;110(12):4123–8. 2. Peffault de Latour R, et al. HemaSphere. 2021;5(S2):109–10. 3. Socie G, et al. Br J Haematol. 2019;185(2):297–310.Keywords: Complement, Paroxysmal nocturnal hemoglobinuria (PNH), Thrombosis